Phencyclidine is known to allosterically increase the apparent affinity of the dihydropyridine (tritiated nitrendipine) calcium antagonist binding site in a lysed synaptosomal membrane preparation of rat forebrain. Treatment of a similar preparation of mouse forebrain with 4-isothiocyanato-1-(1-phenylcyclohexyl) piperidine (FOURPHIT), an acylating phencyclidine derivative, resulted in a concentration dependent (.1-10MuM), irreversible, increase in the apparent affinity of tritiated nitrendipine in contrast to the effects of phencyclidine which were reversible. The FOURPHIT isomer, 1-[1-(3-isothiocyanatophenyl) cyclohexyl]piperidine (METAPHIT), (10 MuM) also irreversibly increased the apparent affinity of tritiated nitrendipine, but was much less efficacious than FOURPHIT. Phencyclidine blocked the irreversible increase in the apparent affinity of tritiated nitrendipine produced by FOURPHIT. The interactions of multivalent cations and the calcium antagonist diltiazem with the tritiated nitrendipine binding site were altered following treatment of membranes with FOURPHIT. These studies suggest that FOURPHIT irreversibly interacts with the same sites as PCP to alter the binding of nitrendipine and thus may be a useful tool with which to further probe both the behavioral and biochemical interactions between phencyclidine and the dihydropyridine calcium antagonist binding site. METAPHIT was previously reported to acylate the classical PCP receptor believed to mediate many of the behavioral effects of PCP. FOURPHIT, however failed to acylate this site under the same conditions, indicating structural specificity for this interaction.